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Wnt-3a Helps the Segmentation Clock Tick

Somitogenesis is the vertebrate developmental process that leads to the formation of the axial skeleton. It is thought that an oscillating mechanism causes cells in the presomitic mesoderm (PSM) to rhythmically activate and inhibit gene transcription.1 The result is waves of gene expression that move in a posterior-to-anterior direction in the PSM to form successive individual somites in the embryo. The oscillating mechanism, termed the segmentation clock, responsible for driving this rhythmic gene expression is unknown. Several models describe the segmentation clock theorizing a timing mechanism that regulates somitogenesis.2-5 Clock-driven cyclically expressed genes, such as c-hairy1, c-hairy2, hes1, hey2, her1, and lfng have been identified in the PSM.3,5 While Notch appears to drive the rhythmic expression of these genes, it may or may not be a part of the clock itself since elimination of Notch affects segmentation differently depending on the context.3

Wnt proteins are recognized as important signaling molecules in a variety of cell types and animal models. Wnt signaling regulates developmental processes such as cell fate determination, polarity, proliferation, and tissue patterning.6 A recent study by Aulehla et al. proposes a model in which Wnt-3a controls the segmentation process via a negative feedback loop with Axin2 (Figure 1A) and that Wnt-3a and Axin2 are expressed in a gradient across the PSM (Figure 1B).5 Wnt-3a activates the transcription of Axin2. Axin2, however, is a negative regulator in the Wnt/beta-catenin signaling cascade such that when Axin2 levels are high, Wnt-3a signaling is low.5,7 At the same time, Wnt-3a also promotes Axin2 degradation. As Axin2 levels decline, Wnt-3a signaling is disinhibited thereby allowing Wnt-3a activity to increase again (Figure 1A).5,7 With each wave of Wnt cycling, a gradient of Wnt-3a protein and signaling activity propagates across the PSM. The amplitude of this Wnt wave slowly decays as it moves anteriorly across the PSM. This damped oscillation halts in the anterior PSM as the pattern is interrupted and somite borders are formed (Figure 1B).1,5